Amide-Linked C4″-Saccharide Modification of KRN7000 Provides Potent Stimulation of Human Invariant NKT Cells and Anti-Tumor Immunity in a Humanized Mouse Model,ACS Chemical Biology

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Amide-Linked C4″-Saccharide Modification of KRN7000 Provides Potent Stimulation of Human Invariant NKT Cells and Anti-Tumor Immunity in a Humanized Mouse Model
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-12-09 , DOI: 10.1021/acschembio.0c00707
Noemi Alejandra Saavedra-Avila , Santosh Keshipeddy ₁ , Matthew J Guberman-Pfeffer ₁ , Ayax Pérez-Gallegos , Neeraj K Saini , Carolina Schäfer ₂ , Leandro J Carreño ₂ , José A Gascón ₁ , Steven A Porcelli , Amy R Howell ₁

Affiliation

Activation of invariant natural killer T (iNKT) cells by α-galactosylceramides (α-GalCers) stimulates strong immune responses and potent anti-tumor immunity. Numerous modifications of the glycolipid structure have been assessed to derive activating ligands for these T cells with altered and potentially advantageous properties in the induction of immune responses. Here, we synthesized variants of the prototypical α-GalCer, KRN7000, with amide-linked phenyl alkane substitutions on the C4″-position of the galactose ring. We show that these variants have weak iNKT cell stimulating activity in mouse models but substantially greater activity for human iNKT cells. The most active of the C4″-amides in our study showed strong anti-tumor effects in a partially humanized mouse model for iNKT cell responses. In silico analysis suggested that the tether length and degree of flexibility of the amide substituent affected the recognition by iNKT cell antigen receptors of the C4″-amide substituted glycolipids in complex with their antigen presenting molecule CD1d. Our findings establish the use of stable C4″-amide linked additions to the sugar moiety for further exploration of the immunological effects of structural modifications of iNKT cell activating glycolipids and highlight the critical need for more accurate animal models to assess these compounds for immunotherapeutic potential in humans.

中文翻译：

KRN7000 的酰胺连接 C4"-糖修饰在人源化小鼠模型中提供了对人类不变 NKT 细胞和抗肿瘤免疫的有效刺激

α-半乳糖苷神经酰胺 (α-GalCers) 激活不变的自然杀伤 T (iNKT) 细胞会刺激强烈的免疫反应和有效的抗肿瘤免疫。已经评估了糖脂结构的许多修饰，以获得这些 T 细胞的活化配体，这些 T 细胞在诱导免疫反应方面具有改变和潜在的有利特性。在这里，我们合成了原型 α-GalCer KRN7000 的变体，在半乳糖环的 C4"-位置上具有酰胺连接的苯基烷烃取代。我们表明，这些变体在小鼠模型中具有较弱的 iNKT 细胞刺激活性，但对人类 iNKT 细胞的活性显着增强。我们研究中最活跃的 C4"-酰胺在 iNKT 细胞反应的部分人源化小鼠模型中显示出强烈的抗肿瘤作用。电脑模拟分析表明，酰胺取代基的系链长度和柔性程度影响了 iNKT 细胞抗原受体对 C4"-酰胺取代糖脂与其抗原呈递分子 CD1d 复合物的识别。我们的研究结果确立了使用稳定的 C4"-酰胺连接添加到糖部分以进一步探索 iNKT 细胞激活糖脂的结构修饰的免疫学效应，并强调迫切需要更准确的动物模型来评估这些化合物在免疫治疗中的潜力人类。

更新日期：2020-12-18

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